PROJECT SUMMARY The initial steps of vision, the transduction and encoding of physical light stimuli into neural signals, occur in the retina, an out-pocketing of the diencephalon of the brain that lines the back of the eye. Retinal circuits are reconfigured according to the prevailing illumination conditions through the action of modulatory retinal neurotransmitters such as dopamine. The long-term goal of the line of research proposed here is to elucidate the underlying cellular and molecular mechanisms by which retinal function is reconfigured by neuromodulatory signals. For the upcoming award period, we propose to focus on two critical areas in retinal neurobiology [unreadable] How connexin channels and hemichannels participate in gap junctional coupling between horizontal cells and may contribute to feedback at the first visual synapse, and how retinal dopaminergic neurons, the source of retinal dopamine, are regulated by light and how they reconfigure retinal circuits. We propose the following 3 specific aims: Aim I: Using the zebrafish molecular genetic model system we will combine electrophysiological analysis of native horizontal cell gap junction and hemichannel currents with connexin gene manipulation to define the roles of connexin channels in horizontal cell coupling and feedback. Aim II. Using a transgenic mouse model developed in our laboratory that enables in situ recording from dopaminergic amacrine neurons (DA neurons), we will further define the synaptic mechanisms regulating sustained, transient, and resting DA neuron activity. Aim III. Using a retina-specific tyrosine hydroxylase (TH) knockout mouse model developed in our laboratory, we will determine the effects of long-term dopamine depletion on dopamine neurons, ganglion cells, and on overall visual function. Completion of these aims will provide information fundamental for understanding normal retinal function and will contribute to our understanding of clinically relevant dopaminergic mechanisms associated with photoreceptor degeneration, myopia, and visual deficits in Parkinsonism and diabetic retinopathy.